Endothelins (ET) are a family of vasoactive peptides. Since their discovery in 1988, ET have been investigated for their physiological function and potential pathological role in cardiovascular disease. Three members of the family, ET-1, ET-2 and ET-3, are produced in a variety of tissues including vascular endothelium, vascular smooth muscle, and myocardium, where they act via endocrine and paracrine pathways to modulate vasomotor tone, cell proliferation, and the renin-angiotensin-aldosterone system. ET-1 is a biologically active 21 amino acid peptide that is cleaved by endothelin converting enzyme from big ET-1, a 38 amino acid peptide possessing 1/100 the biologic activity of the mature ET. ET-1 binds to two types of endothelin receptors, ETA and ETB. ETA receptors have the greatest affinity for ET-1 and are expressed predominately in vascular smooth muscle cells, where their activation mediates vasoconstriction. ETB receptors are found on endothelial cells and, to a much lesser extent on vascular smooth muscle cells. Stimulation of smooth muscle cell ETB receptors leads to the release of endothelium-dependent vasodilators, nitric oxide and prostacyclin. Pulmonary ETB receptors have been implicated in the clearance of ET from plasma. The myocardium expresses both ETA and ETB receptors, although ETA receptors predominate and their activation by exogenously applied ET produces a positive inotropic response. Patients with more severe heart failure have elevated plasma ET levels. The magnitude of the elevated levels is positively correlated with NYHA Functional Class and left ventricular and diastolic volume. It is inversely related to left ventricular ejection fraction, cardiac index, and survival (in advanced heart failure). Plasma ET levels measured during exercise also appear to be inversely related to exercise capacity. Patients with the highest ET-1 levels at the time of maximal exercise achieved the lowest levels of maximum oxygen consumption. Blocking the effects of ET has the potential to ameliorate the clinical signs and symptoms of heart failure. Based on its preclinical profile, the ETA selective receptor antagonist BMS-193884 is expected to be an effective therapeutic intervention in patients with heart failure. To define a therapeutic dose range, this initial phase II study will evaluate the hemodynamic effects of several single, oral doses of BMS-193884 in patients receiving conventional, concomitant therapy, including ACE1.